Indole derivatives



United States Patent 3,502,667 INDOLE DERIVATIVES Michio Nakanishi andRyosuke Kobayashi, Nakatsu, and Masahiro Torigoe, Chikujo-gun, Japan,assignors to goshitomi Pharmaceutical Industries, Ltd., Osaka,

apan No Drawing. Filed Mar. 2, 1967, Ser. No. 620,246 Claims priority,application Japan, Mar. 2, 1966, 41/13,094; Dec. 10, 1966, 41/81,197;Dec. 16, 1966, 41/ 82,570

Int. Cl. C0711 27/56 U.S. Cl. 260247.2 37 Claims ABSTRACT OF THEDISCLOSURE Compounds of the formula wherein X is H, halogen, lower alkylor lower alkoxy; Y is C C alkylene or Z-hydroxytrimethylene; Z is loweralkyl-amino, di-lower alkyl-amino, l-pyrrolidinyl, piperidino,morpholino or 4-lower alkyl-l-piperazinyl; and R is amino, loweralkyl-amino, hydroxyl or lower alkoxy, are useful as drugs for asthmaand as antispasmodics.

This invention relates to therapeutically useful indole derivatives ofthe formula wherein X is H, halogen (e.g. Cl), lower alkyl or loweralkoxy;

Y is C -C alkylene or 2-hydroxytrimethylene;

Z is lower alkyl-amino, di-lower alkyl-amino, l-pyrrolidinyl,piperidino, morpholino or 4-lower alkyl-l-piperazinyl; and

R is amino, lower alkyl-amino, hydroxyl or lower alkoxy,

and pharmaceutically acceptable acid addition salts thereof. The termlower means that the alkyl or alkoxy contains not more than four carbonatoms.

The compounds (I) of the invention can be prepared by reacting an indolecompound of the formula X OQ,

oon liI (II) with a compound of the formula Q'-Z (IH) 3,502,667 PatentedMar. 24, 1970 be used as an acid acceptor to bind the hydrogen halide.

formed by the reaction. Such alkaline or basic substance is, forexample, an alkaline hydroxide, an alkaline carbonate, an alkalinehydrogen carbonate, an alkaline hydride, an alkaline alkoxide,triethylamine, N,N-dimethyl aniline, N,N-diethylaniline, pyridine oranother organic base. An excess of the starting amine (III) where Q is Hcan be used also as acid acceptor. When an amine (III) (Q=H) with a lowboiling point is a starting material, the reaction is preferably carriedout under pressure in a pressure container or in an autoclave. Moderateheating or warming is favorable for the reaction.

When the starting indole compound (II) is one where R is OH, an ester(in Formula I, R=OY-Z) or an ammonium salt (in Formula I, R=OH.HZ) isformed. The ester or salt can easily be hydrolyzed, for example, bytreatment with an alkaline hydroxide, followed by treatment of theresulting alkaline carboxylate with an acid such as hydrochloric acid.

The compounds of Formula I in which R is OH can also be derived from thecorresponding esters (in Formula I, R=lower alkoxy) or amines (inFormula I, R=amino or lower alkyl-amino) by a per se conventionalmethod, and vice .versa. The amides can also be prepared from thecorresponding lower alkyl esters.

The compounds (I) can be converted to pharmaceutically acceptable acidaddition salts such as hydrochloride, sulfate, nitrate, phosphate,formate, acetate, propionate, oxalate, benzoate, salicylate, nicotinate,fumarate, male ate, phthalate, anthranilate, succinate, citrate,glutarate, tartrate, malate and picrate, in per se conventional manner.

The compounds (I) and the pharmaceutically acceptable acid additionsalts thereof are all useful as antispasmodic agents and as drugs forthe treatment of asthma.

Antihistaminic (Antihist), antiacetylcholine (AntiAch), anti-serotonin(Anti SHT), and barium chloride antagonizing (Anti Ba++) activities of arepresentative compound of the invention, namely, ethyl3-(3-dimethylaminopropoxy)-2-indolecarb0xylate hydrochloride (IDY-IOOl),for example, as determined with the isolated intestine of the guinea pigand compared with those of papaverine hydrochloride areas follows (interms of ED (mg./kg.)):

IDY-IOOl Papaverine.HCl

Antihist 0. 2 2 AntiAch 3. 5 6 Anti 511T 6 25 Anti Ba++ 9 10 EDw (50%protecting dose, mg./kg.)

Spasm ID Y-1001 Ephedrine. H01

Histamine 0.1 12 Acetylcholine 2. 5 1. 8 Serotonin 2 The compounds (I)and salts thereof as antispasmodics are administered orally as tablets,parenterally by subcutaneous, intramuscular or intravenous injection, orrectally as suppositories. The usual dose for adults is 10-50 milligrams3 times daily.

For the treatment of asthma, inhalation of aerosols containing compound(I) or a salt thereof is recommended. The daily usual dose for adults isabout 30-150 milligrams.

The following examples represent presently preferred illustrativeembodiments.

EXAMPLE 1 A mixture of 35 grams of ethyl 3-hydroxy-2-indolecarboxylate,22 grams of S-dimethylaminopropyl chloride, 12 grams of anhydrouspotassium carbonate and 100 milliliters of dimethylformamide was heatedon a water bath at 70 C., with stirring for 5 hours, and then thereaction mixture was poured into 300 milliliters of ice water. Theseparated oil layer was taken up with diisopropyl ether, the other layerextracted with hydrochloric acid, and the extract neutralized with anaqueous solution of potassium carbonate. The separated oil layer wastaken up with diisopropyl ether, dried over anhydrous potassiumcarbonate and treated with a theoretically required amount of ethanolichydrochloric acid to precipitate ethyl3-(3-dimethylaminopropoxy)-2-indolecarboxylate hydrochloride. Theproduct was recrystallized from an ethanoldiisopropyl ether mixture togive 34 grams of the purified product with a melting point of 156-l57 C.The yield was 65.8%.

Analysis.-Calculated for C H N 'O -HCl (percent): C, 58.81; H, 7.09; N,8.57. Found (percent): C, 58.26; H, 6.96; N, 8.67.

EXAMPLE 2 Fifty milliliters of dimethyl sulfoxide was added to a mixtureof 4.1 grams of ethyl 3-hydroxyindole-2-carboxylate, 3.5 grams ofZ-dimethylaminoethyl chloride hydrochloride and 3 grams of anhydrouspotassium carbonate, and the whole was heated at 80 C. on a water bathfor 3 hours with stirring. The reaction mixture was cooled, and pouredinto water. The separated oil was taken up with diisopropyl ether, theextract dried over anhydrous potassium carbonate, the ether distilledoff, and the oily residue heated in 2 milliliters of 28% ethanolichydrochloric acid. After cooling the resultant solution, a small amountof diethyl ether was added to yield a precipitate, which wasrecrystallized from an ethanol-diisopropyl ether mixture. Thus fivegrams of ethyl 3-(2-diethylaminoethoxy)-2-indolecarboxylatehydrochloride with a melting point of 125127 C. was obtained. The yieldwas 66.2%.

Analysis.Calculated for C H ClN O (percent): C, 59.90; H, 7.39; N, 8.22.Found (percent): C, 59.91; H, 7.27; N, 8.24.

EXAMPLE 3 A mixture of 14 grams of ethyl 3-(3-chloropropoxy)-2-indolecarboxylate, 7 grams of isopropylamine and 50 milliliters of 99%ethanol in a pressure receptacle was heated at 80 C. for 5 hours. To thereaction mixture 200 milliliters of water was added, and the whole wasextracted with diisopropyl ether. The extract was dried over anhydrouspotassium carbonate, and treated with 38% ethanolic hydrochloric acid.Ethyl 3-(3-isopropylaminopropoxy)-2-indolecarboxylate hydrochloride witha melting point of 215 C. (decomposition) was obtained as a precipitatein 82.3% yield (16 grams).

Analysis.Calculated for C H ClN O (percent): C, 59.90; H, 7.39; N, 8.22.Found (percent): C, 59.75; H, 7.51; N, 8.25.

EXAMPLE 4 A mixture of 5.6 grams of ethyl 3-(3-chloropropoxy)-2-indolecarboxylate, 2 grams of pyrrolidine and 100 milliliters of toluenewas heated at 80 C. for 4 hours. The reaction mixture was washed withwater and extracted with 10% hydrochloric acid. The extract was madealkaline with 10% aqueous sodium hydroxide solution. The separated oilwas taken up with toluene, and the toluene solution, after drying overpotassium carbonate, treated with alcoholic hydrochloric acid to giveethyl 3-(3-(l-pyrrolidinyl)propoxy) 2 indolecarboxylate hydrochloride.After recrystallization from ethanol the hydrochloride weighed 5.6 grams(75% yield) and melted at 198 C.

Analysis.Calculated for C H ClN O (percent): C, 61.27; H, 7.14; N, 7.94.Found (percent): C, 60.86; H, 7.31; N, 7.76.

EXAMPLE 5 A mixture of 7 grams of 3-(3-chloro-2-hydroxypropoxy) N methyl2 indolecarboxamide and 30 milliliters of 35% aqueous methylaminesolution in a pressure receptacle was heated at C. for 5 hours. Thereaction mixture was poured into milliliters of water and extracted withchloroform. The extract was shaken with 10% aqueous hydrochloric acid,the aqueous layer made alkaline with 10% sodium hydroxide and extractedwith chloroform. The chloroform extract was dried over sodium sulfate,then the solvent distilled off, and the residue recrystallized fromethyl acetate to give 3-(2-hydroxy-3- methyla-minopropoxy) 2 indole Nmethyl carboxamide melting at 156-l59 C. in 51.7% yield.

Analysis.Calculated for C H N O (percent): C, 60.64; H, 6.91; N, 15.15.Found (percent): C, 60.52; H, 6.80; N, 14.87.

The following compounds were obtained in a similar manner as in theforegoing examples (chemical name, melting point and recrystallizationsolvent being given):

3- (3 -dimethylaminopropoxy) -2-indolecarboxamide,

157 C., aqueous ethanol;

3-(3-isopropylaminopropoxy)-2-indole-N-methylcarboxamide, 80-82 C.,aqueous ethanol;

ethyl 5-methoxy-3 3-dimethylaminopropoxy -2-indolecarboxylatehydrochloride, 147148 C., ethanoldiisopropyl ether mixture;

ethyl 3-(3-piperidinopropoxy)-2-indolecarboxylate hydrochloride, 2082l0C., ethanol-diisopropyl ether mixture;

3-(2-piperidinopropoxy)-2-indole-N-methyl-carboxamide, whose crystalscontain half a molecule of water of crystallization, 198 C., ethanol;

ethyl 3-(3-morpholinopropoxy)-2-indolecarboxylate hydrochloride, 207-208C., ethanol-diisopropyl ether mixture;

ethyl 3- 2-methyl-3 -morpholinopropoxy) -2-indolecarboxylatehydrochloride, 207-209 C., ethanoldiisopropyl ether mixture;

3-(3-morpholinopropoxy)-2-indolecarboxamide,

180-l82 C., aqueous ethanol;

ethyl 5-ch1oro-3-(3-morpholinopropoxy) -2-indolecarboxylatehydrochloride, whose crystals contain A molecule of water ofcrystallization, 220- 220.5 C., ethanol;

ethyl 5-methyl-3- 3-morpholinopropoxy) -2-indolecarboxylate, 119-120 C.,ethanol;

ethyl 5-methoxy-3 3-morpholinopropoxy -2-indolecarboxylatehydrochloride, whose crystals contain half a molecule of water ofcrystallization, 182- 183 C., ethanol;

ethyl 5-methoxy-3- 2-morpholinoethoxy) -2-indolecarboxylate picrate,2l9-220 C., ethanol;

ethyl 3- (3-dimethylaminopropoxy) -5-methyl-2- indolecarboxylatepicrate, 171.5l72.5 C.;

ethyl 5-methyl-3-(2-piperidinopropoxy)-2-indolecarboxylatehydrochloride, 213 C., ethanol;

ethyl 3-(3-diethylaminopropoxy)-2-indolecar-boxylate hydrochloride, 164C., ethanol-diisopropyl ether mixture;

ethyl 3- 2-morpholinoethoxy) -2-indolecarboxylate hydrochloride, 208 C.,ethanol-diisopropyl ether mixture;

5-methyl-3-(3-morpholinopropoxy)-2-indole-N- methyl-carboxamide, 181-182C., ethanol;

3-(3- (4-methyl-1-piperazinyl)propoxy) -2-indole- N-methyl-carboxamide,115-116 C., diisopropyl ether;

ethyl 3- 3- 4-methyll-piperazinyl) propoxy -2- indolecarboxylatedihydrochloride, 250 C. (decomposition), ethanol-diisopropyl ethermixture;

ethyl 5-methoxy-3- (3-(4-methyl-1-piperazinyl)propoxy)-2-indolecarboxylate dihydrochloride,226- 227 C., methanol;

ethyl 3-(2-hydroxy-3-dimethylaminopropoxy)-2- indolecarboxylatehydrochloride, methanol-diisopropyl ether mixture;

ethyl 3-(2-hydroxy-3 -piperidinopropoxy)-2- indolecarboxylatehydrochloride, 203 C. (decomposition with foaming), ethanol;

ethyl 3- (2-hydroxy-3 morpholinopropoxy) -2- indolecarboxyl'atehydrochloride, 177-l79 C., 95 ethanol;

ethyl 3-(2-hydroxy-3-(4-methyl-l-piperazinyl)-propoxy)-2-indolecarboxylate dihydrochloride, Whose crystals containhalf a molecule of water of crystallization, 228-229 C., 95% ethanol.

EXAMPLE 6 A solution of 5.7 grams of3-(3-chloropropoxy)-2-indolecarboxylic acid and 6 grams of piperidine in50 milliliters of ethanol was heated with stirring on a water bath at 50C. for 5 hours. Then the ethanol was distilled off, the residuedissolved in a small amount of water, an aqueou solution containing 0.8gram of sodium hydroxide added to the solution, the whole evaporated,and the residue suspended in ethanol. To the suspension there was added38% ethanolic hydrochloric acid, the mixture stirred and filtered toremove insoluble matter, and diisopropyl ether added portionwise to thefiltrate. The formed precipitate was recrystallized from anethanol-diisopropyl ether mixture to give 3-(3-piperidinopropoxy)-2-indolecarboxylic acid hydrochloride melting at 172 C. withdecomposition in 43.4% yield.

Analysis.Calculated for C17H2 ClN O (percent): C, 60.27; H, 6.84; N,8.27. Found (percent): C, 60.12; H, 6.97; N, 8.10.

EXAMPLE 7 A mixture of 1.4 grams of3-hydroxy-5-methoxy-2-indolecarboxylic acid, 2.8 grams of potassiumcarbonate, 1.7 grams of 3-morpholinopropyl chloride and milliters ofdimethylformamide was heated with stirring at 80 C. for 6 hours. To thereaction mixture there was added an aqueous solution of 0.2 gram ofsodium hydroxide, and the Whole was refluxed for 2 hours, cooled,neutralized with dilute hydrochloric acid and evaporated to. drynessunder reduced pressure. The residue was extracted with hot ethanol.After removing the ethanol by distillation, the residue wasrecrystallized from methanol to give 1.1 grams of 5-methoxy-3-( 3morpholinopropoxy) 2 indolecar- =boxylic acid melting at l17ll9 C. Theyield was 45.1%.

Analysis-Calculated for C17H22O5N2 (percent): C, 61.06; H, 6.63; N,8.38. Found (percent): C, 60.86; H, 6.80; N, 8.27.

EXAMPLE 8 A solution of 0.5 gram of sodium hydroxide in 3 milliliters ofwater was added to a solution of 0.6 gram of ethyl5-methoxy-3-(3-morpholinopropoxy) 2 indolecarboxylate in 2 millilitersof water, and the whole refluxed for 2 hours. Then 5 milliliters ofwater was added, and the mixture adjusted to pH 7 with hydrochloricacid. Then the water was distilled off. The residue was treated as inExample 7 to give 0.2 gram of 5-methoxy-3-(3-morpholinopropoxy)-2-indolecarboxylic acid melting at 118- 119 C.

Similarly as in Examples 6, 7 or 8, the following were prepared:

3-(3-dimethyla-minopropoxy)-2-indolecarboxylic acid hydrochloride, 148C. (decomposition), ethanol-diisopropyl ether mixture;

3-(3-(l-pyrrolidinyl)propoxy) 2 indolecarboxylic acid (intramolecularsalt) whose crystals contain half a molecule of water ofcrystallization, 180 C. (decomposition), ethanol;

3-(3-morpholinopropoxy)-2-indolecarboxylic acid hydrochloride, 178 C.(decomposition), methanol-diisopropyl ether mixture; and

3-(3-(4-methyl-1-piperazinyl)propoxy)-2 indolecarboxylic aciddihydrochloride, whose crystals contain 2 molecules of water ofcrystallization, 120 C. (decomposition), aqueous ethanol.

EXAMPLE 9 A mixture of 0.7 gram of ethyl5-methyl-3-(3-morpholinopropoxy)-2-indolecarboxylate, 5 milliliters of a35% aqueous methylamine solution and 5 milliliters of ethanol was heatedin a pressure receptacle at C. for 15 hours. The reaction mixture waspoured into milliliters of water, and the precipitate formed was washedwith water, dried and recrystallized from ethanol to give 0.5 gram(77.2% yield) of 5-methyl-3-(3-morpholinopropoxy)-2-indole-N-methyl-carboxamide melting at 182 C.

Analysis.Calculated for C H O N (percent): C, 65.23; H, 7.60; N, 12.68.Found (percent): C, 64.98; H, 7.81; N, 12.62.

The following formulae correlate structure and nomenclature according tothe present application.

Example 1.Ethyl 3-(3-dimethylaminopropoxy)-2- indolecarboxylate Example3.Ethyl 3-(3-isopropylaminopropoxy)-2- indolecarboxylate Example4.-Ethyl 3-(3-(1-pyrrolidinyl)propoxy)-2 indolecarboxylate Example5.3-(2-hydroxy-3-methylaminopropoxy)- 2-indole-N-methyl carboxamide CH5H.

Example 6.-3- 3-piperidinopropoxy -2-indole- 130 CHZO Example9.-me'thyl-3- (3-morphoiinoprop0xy 2-indole'N-methyl carboxamide Havingthus disclosed the invention, what is claimed 1. A member selected fromthe group consisting of compounds of the formula.

and :the pharmaceutig i ally acceptable acid addition salts thereof,wherein X H, halogen, alkyl or alkoxy,

Y is C C alkylene, V

Z is alkyl-amino, di-alkyl-amino, l-pyirolidinyl, pipe ridino,morpholino or 4-loWer alkg l-l-piperazinyl, and

R is amino, alkyl-amino, hydroxyl or alkoXy;

alkyl and alkoxy in each occurrence thereof containing not more thanfour carbon atoms.

2. A compound according to claim 1, said compound being in the form of ahydrochloride.

3. A compound according to claim 1, said compound being ethyl 3(3-dirnethylaminopropoxy)2 indolecarboxylat e.

4. A compound according to claim 1, said compound being ethyl 3 (3isopropylaminopropoxy)-2-indolecarboxylate. e e

5. A compound according to claim 1, said compound being 3 (3dimethylaminopropoxy) 2 indolecarboxamide.

6. A compound according to claim 1, said compound being 3 (3isopropylaminopropoxy) N methyl 2- indolecarboxamide.

7. A compound according to claim 1, said compound being ethyl 3 (3dimethylaminopropoxy) 5 methoxy- 2-indolecarboxylate= 8. A compoundaccording to claim 1, said compound being ethyl 3 (3pyrrolidino)propoxy) 2 indolecarboxylate.

9. A compound according to claim 1, said compound being ethyl 3 (3piperidinopropoxy) 2 indolecarboxylate.

10. A compound according to claim 1, said compound being ethyl 3 {3diet'nylaminopropoxy) 2 indolecarboxylate.

11. A compound according to claim 1, said compound being ethyl 3 (3morpholinopropoxy) 2 indolecarboxylate.

12. A compound according to claim 1, said compound *being ethyl 3 (2methyl 3 morpholinopropoxy) 2- indolecarboxylate.

13. A compound according to claim 1, said compound being ethyl 3 (3 (4methyl 1 pip-erazinyl) propoxy)- 2-indolecarboxylate.

14. A compound according to:c1aim 1, said compound being 3 (3morpholinopropoxy) 2 indolecarboxamide. I

15. A compound according to claim 1, said compound being 3 (2piperidinopropoxy) 2 indole N methylcarboxamide.

16. A compound according to claim 1, said compound being 3 (3 (4 methyl1 piperazinyhpropoxy) 2- indole-N-methyl-carboxamide.

17. A compound according to claim 1, said compound being ethyl 5 chloro3 3 morpholinopropoxy) 2- indolecarboxylate.

18. A compound according to claim 1, said compound being ethyl 5 methyl(3 (3 morpholinopropoxy) 2- indolecar'poxylate 1'9. A compound accordingto claim 1, said compound being ethyl 5 methoxy 3 (3 morpholinopropoxy)2- indolecarboxylate. V

' 20. A compound according to claim 1, said compound being ethyl 5methoxy 3 (3 (4 methyl 1 piperazinyl)propoXy)-2 indolccarboxylate.

21. A compound according to claim 1, said conftpound being 5 methyl 3 (3morpholinopropoxy) 2 indole- N-methyl-carb oxamide. W

22; A compound according to claim 1, said compound being ethyl 5 methoxy3 (2 morpholinoethoxy) 2- indolecarboxylate.

23. A compound according to claim 1, said compound being 3 (3piperidinopropoxy) 2 indolecarboxylic acid.

24. A compound according to claim 1, said compound being 3 {3dimethylaminopropoxy) 2 indolecarboxylic acid. 1 g

25. A compound according to claim 1, said compound being 3 '(3 (lpyrrolidinyDpropoxy) 2 indolecarboxylic acid.

26. A compound according to claim 1, said compound being 3 (3morpholinopropoxyy- 2 indolecarboxylic acid. e

27. A compound according to claim 1, said compound being 3 (3 (4 methyl1 piperazinyDpropoxy) 2- indolecarboxylic acid. o

28. A compound according to claim 1, said compound being 5 methoxy 3 (3morpholinopropoxy) 2 indoleoarboxylic acid.

29. A compound according to claim 1, said compound being ethyl 3 (3dimethylaminopropoxy) 5 methyl- 2-indolecarboxylate.

30. A compound according to claim 1, said compound being ethyl 5 methyl3 (2 piperidinopropoxy) 2- indolecarboxylate.

31. A compound according to claim 1, said compound being ethyl 3 (3dimethylamino 2 hydroxypropoxy)- 2-indolecarboxylate.

32. A compound according to claim 1, said compound being ethyl 3 (2hydroxy 3 piperidinopropoxy) 2- indolecarboxylate.

33. A compound according to claim 1, said compound being ethyl 3 (2hydroxy 3 morpholinopropoxy) 2- indolecarboxylate.

34. A compound according to claim 1, said compound being ethyl 3 (2hydroxy 3 (4 methyl l pipera- Zinyl)propoxy)-2-indolecarboxylate.

35. A compound according to claim 1, said compound being 3 (2 hydroxy 3methylaminopropoxy) N- methyl-Z-indolecarboxamide.

36. A compound according to claim 1, said compound being ethyl 3 (2diethylaminoethoxy) 2 indolecarboxyiate.

37. A compound according to claim 1, said compound ALEX MAZEL, PrimaryExaminer being ethyl 3 (2 morpholinoethoxy) 2 indolecar- A M T TIGHEAssistant Examiner boxylatc.

References Cited US Cl.

UNITED STATES PATENTS 5 260268, 294, 294.3, 295.5, 326.13, 326.14;424-232,

3,376,300 4/1968 Shen 260-247.2 248, 250, 266, 267, 274

